Project Summary Introduction of prophylactic human papillomavirus (HPV) vaccines has the potential to dramatically decrease morbidity and mortality from anogenital and oropharyngeal cancers. However, data from vaccine clinical trials cannot predict vaccine effectiveness in ?real-world? community settings, and introduction of a 9-valent (in addition to a 2- and 4-valent) vaccine in 2015 and reduced dosing schedules (from 3 to 2 doses) in 2016 could further modify vaccine effectiveness. The impact of vaccine introduction can be efficiently and accurately evaluated by HPV surveillance studies that assess vaccine effectiveness, herd protection, cross-protection (decrease in HPV types genetically related to vaccine types), and type replacement (increase in non-vaccine- type HPV due to a reduction in vaccine types). We previously conducted 4 HPV surveillance studies in women (2006-2017) and 2 in men (2013-2017). Among women, we found evidence for vaccine effectiveness (but lower effectiveness with 1 vs. 3 doses), herd protection, and cross-protection; no evidence for type- replacement; and an unexpected increase in non-vaccine-type HPV in unvaccinated women. Among men, we found preliminary evidence for vaccine effectiveness and herd protection. Continued investigation through the proposed renewal is essential to achieve the following objectives: 1) assess the effects of 9-valent vaccine introduction and reduced dosing schedules on effectiveness, 2) elucidate long-term trends in herd protection, 3) identify signals of diminished cross-protection or emerging type-replacement, and 4) determine mechanisms for increases in non-vaccine-type HPV in unvaccinated women. The specific aims are to: 1) determine long- term trends in 4-valent - and emerging trends in 9-valent - HPV prevalence among vaccinated women (2006- 2023) and men (2013-2023) to assess HPV vaccine effectiveness, and among unvaccinated women and men to assess herd protection; 2) assess the differential impact of the number of vaccine doses received on vaccine-type HPV, by age; 3) determine trends in non-vaccine-type HPV prevalence among vaccinated women and men, to examine for persistent cross-protection and emerging type replacement; and 3) explore biological and behavioral mechanisms for the increase in non-vaccine-type HPV in unvaccinated women. Our approach will be to enroll 1,600 women and men in two additional surveillance studies, to characterize the impact of vaccine introduction across a total of 6 time periods in women (2006-2023, N=2,400) and 4 in men (2013- 2023, N=1,600). The proposed research is innovative because the resulting data could shift current research and clinical practice paradigms in the areas of vaccination and virology, and the research plan utilizes novel concepts, approaches and new methodologies to explore mechanisms driving HPV trends. The proposed research is significant because the data will provide key evidence for: 1) vaccination and cervical cancer screening programs; 2) public health communications and risk-reduction counseling; and 3) cost-effectiveness analysis and policy decisions: these will help to reduce disparities and mortality due to HPV-related cancers.